BRPI0616653A2 - compound and pharmaceutically acceptable salts thereof, pharmaceutical formulation, use of a compound, and process for the preparation of a compound - Google Patents

Abstract

COMPOUND AND PHARMACEUTICALLY ACCEPTABLE SALES OF THE SAME, PHARMACEUTICAL FORMULATION, USE OF A COMPOUND, AND, PROCESS FOR THE PREPARATION OF A COMPOUND. The present invention relates to 4,5,6,7-tetrahydropyrrolo [3,2-c] pyridin-4-one and 4,5-dihydropyrrolo [3,2-c] pyridin-4-one compounds of < UM> formula <MV> (I) and processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, methods for their therapeutic use and pharmaceutical compositions containing them.

Description

"COMPOUND AND PHARMACEUTICALLY ACCEPTABLE SALTS OF THE SAME, PHARMACEUTICAL FORMULATION, USE OF A COMPOUND, AND PROCESS FOR PREPARING A COMPOUND"

FIELD OF INVENTION

The present invention relates to certain compounds of 4,5,6,7-tetrahydropyrolo [3,2-c] pyridin-4-one and 4,5-dihydropyrrolo [3,2-c] pyridin-4-one formula (I ), processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, methods for their therapeutic use, and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Certain CBi modulators (known as antagonists or inverse agonists) are known to be useful in the treatment of obesity, psychiatric and neurological disorders (WO 01/70700 and EP

56564). WO 03/027114 describes the use of 1,5,6,7 = tetrahydropyrrolo [3,2-c] pyridine 1,3,5,6-tetrahydropyrrolo [3,2-c] pyridin-4-one derivatives, for the treatment of obesity. However, there is a need for CB modulators with improved physicochemical properties and / or DMPKe properties and / or pharmacodynamic properties.

DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I

<formula> formula see original document page 2 </formula>

wherein R1 represents a C3-7 alkyl group substituted by one or more fluoro or R1 represents a C1-7 alkylsulfonyl group substituted by one or more fluoro;

R represents cyano, or a C1 -C4 alkyl group optionally substituted by hydroxy or a group NRaRb wherein Ra and Rb are independently H or a C1-C3 alkyl group; R3 represents piperidin-1-yl or cyclohexyl each of which being optionally substituted by one or more groups selected from hydroxy, fluoro or an NRcRd group wherein R0 and Rd independently represent H or a C1 -C3 alkyl group; and

------ is an optional additional bond between positions 6 and 7;

R4 represents chloro, fluoro, cyano or methyl;

η is 1, 2 or 3 and each R4 is independently selected when η> 1;

and pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a compound of formula IA

<formula> formula see original document page 3 </formula>

on what

R1 represents a C3 -C7 alkyl group substituted by one or more fluoro or R1 represents a C1-7 alkylsulfonyl group substituted by one or more fluoro;

R 2 represents cyano, or a C 1 -C 4 alkyl group, optionally substituted by hydroxy or a group NRaRb wherein Ra and Rb are independently H or a C 1 -C 3 alkyl group;

R represents piperidin-1-yl or cyclohexyl each of which optionally is substituted by one or more selected groups of hydroxy, fluoro or an NRc R d group wherein R c and R d is independently H or a C 1 -C 3 alkyl group; and

represents chlorine, fluoro, cyano or methyl;

η is 1, 2 or 3 and each R4 is independently selected when η> 1;

and pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a compound of formula IB

<formula> formula see original document page 4 </formula>

on what

R1 represents a C3-7 alkyl group substituted by one or more fluoro or R1 represents a C1-7 alkylsulfonyl group substituted by one or more fluoro;

R represents cyano, or a C1-4 alkyl group optionally substituted by hydroxy or a group NRaRb wherein Ra and Rb independently represent H or a C1-3 alkyl group;

R3 represents piperidin-1-yl or cyclohexyl each of which being optionally substituted by one or more selected groups of hydroxy, fluoro or an NRcRd group wherein Rc and Rd independently represent H or a C1-C3 alkyl group; eR represents chloro, fluoro, cyano or methyl;

η is 1, 2 or 3 and each R4 is independently selected.

when η> 1;

and pharmaceutically acceptable salts thereof.

Other values of R1, R25 R3 and R4 of the compounds of formula I, formula IA and IB now follow. It is to be understood that such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.

Suitably R 1 represents a C 1-7 alkylsulfonyl group substituted by one or more fluoro, for example 4,4,4-trifluorobutyl-1-sulfonyl, 4-fluorobutyl-1-sulfonyl, 3,3,3-trifluoropropyl 1-sulfonyl, or 3-fluoropropyl-1-sulfonyl. Suitably R 1 represents a C 3-7 alkyl group substituted by one or more fluoro, for example 4,4,4-trifluorobutyl, 4-fluorobutyl, 3,3,3-trifluoropropyl or 3-fluoropropyl. More particularly, R 1 represents a C 3 -C 5 alkylsulfonyl group, terminally substituted by one or more fluoro.

Suitably R is cyano or a C1 -C4 alkyl group optionally substituted by hydroxy, for example methyl, ethyl or hydroxymethyl or a C1 -C4 alkyl group optionally substituted by a group

NRaRb wherein Ra and Rb independently represent H or a C1 -C3 alkyl group, for example aminomethyl, methylaminomethyl or dimethylaminomethyl. Particularly, R2 represents methyl or hydroxymethyl. More particularly, R represents methyl.

Suitably R is piperidin-1-yl or cyclohexyl, each of which is optionally substituted by one or more selected groups of hydroxy, fluoro or an NRcRd group wherein Rc and Rd independently represent H or a C1 -C3 alkyl group, e.g. hydroxypiperidin-1-yl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 2-aminocyclohexyl, 3-aminocyclohexyl, 2-dimethylaminocyclohexyl, 3-dimethylaminocyclohexyl or 4,4-difluorocyclohexyl.

Particularly R3 represents piperidin-1-yl.

Suitably R 4 represents chloro, fluoro, cyano or methyl and η is 1, 2 or 3, for example 2,4-dichloro, 2-chloro, 2-methyl, 2-cyano, 3-cyano, 4-cyano, 3 fluoro-5-cyano or 2-methyl-4-chloro. Particularly R4 represents 2-chloro when η is 1 or R4 represents 2,4-dichloro or 2-chloro-4-fluoro when η 2. More particularly, R4 represents 2-chloro when η is 1 or R4 represents 2,4-dichloro when η is 2.

Suitably, η is 1, 2 or 3. Particularly, η is 2 or 3.

"Pharmaceutically acceptable salt" where such salts are possible includes both pharmaceutically acceptable acid and base addition salts. A pharmaceutically acceptable salt of a compound of formula I is, for example, an acid addition salt of a compound of formula I, which is sufficiently basic, for example, an acid addition salt with an inorganic or organic acid, e.g. a hydrochloride salt, a hydrosulfate salt, a sulfate salt, a methanesulfonate salt, a phenylsulfate salt or a 1,5-naphthalene disulfonate salt or, for example, a salt of a compound of formula I, which is sufficiently acidic with a base.

Throughout the report and the appended claims, a given formula or chemical name will encompass all stereo and optical isomers and racemates thereof, as well as mixtures in different proportions of separate enantiomers, wherein such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and their solvates. , such as, for example, hydrates. The isomers may be separated using conventional techniques, e.g. e.g. chromatography or fractional crystallization. Enantiomers may be isolated by racemate separation, for example, by fractional crystallization, resolution or HPLC. Diastereomers may be isolated by separation of isomeric mixtures, for example, by functional crystallization, HPLC or flash chromatography. Alternatively, stereoisomers may be produced by chiral synthesis of chiral starting materials, under conditions that do not cause cracking or epimerization, or by derivation, with a chiral reagent.

All tautomers, where possible, are included within the scope of the invention. All tautomers, where possible, are included within the scope of the invention. The present invention also encompasses compounds containing one or more isotopes, for example 14C5 11C or 19F and their use as isotopically labeled compounds for pharmacological and metabolic studies.

The present invention also encompasses prodrugs of a compound of formula I, which are compounds that are converted to a compound of formula I in vivo.

The following definitions will apply throughout the report and the accompanying claims.

Unless otherwise stated or indicated, the term "alkyl" denotes a straight or branched alkyl group. Examples of ditaalkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl or t-butyl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and tertiary butyl.

Unless otherwise stated or indicated, the term "halogen" shall mean fluorine, chlorine, bromine or iodine.

Specific compounds of the invention include one or more of the following:

4- [1- (2-chlorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine-2 -yl] phenyl 3,3,3-trifluoropropane-1-sulfonic acid ester

4- [1- (2,4-dichlorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine 3,3,3-trifluoropropane-1-sulfonic acid -2-yl] phenyl ester;

4- [1- (2-chloro-4-fluorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-7

4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-yl] phenyl 3,3,3-trifluoropropane-1-sulfonic acid ester;

1- (2-chlorophenyl) -3-methyl-5-piperidin-1-yl-2- [4- (4,4,4-trifluorobutoxy) phenyl] -1,5,6,7-tetrahydropyrrolo [3.2 -c] pyridine-4-one;

4- [1- (2-chlorophenyl) -5- (2-hydroxycycloexyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2 3,3,3-trifluoropropane-1-sulfonic acid phenyl ester;

4- [1- (2,4-dichlorophenyl) -5- (2-hydroxycycloexyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin 3,3,3-trifluoropropane-1-sulfonic acid -2-yl] phenyl ester;

4- [1- (2-chlorophenyl) -5- (3-hydroxycycloexyl) -3-methyl-4-οχο-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2 3,3,3-trifluoropropane-1-sulfonic acid phenyl ester;

4- [1- (2-chlorophenyl) -5-cyclohexyl-3-methyl-4-oxo-4,5,6,7-tetrahydro-1'-pyrrolo [3,2-c] pyridin-2-yl] phenyl ester 3,3,3-trifluoropropane-1-sulfonic acid;

4- [1- (2,4-dichlorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5-dihydro-1H-pyrrolo [3,2-c] pyridin-2-yl ] 3,3,3-trifluoropropane-1-sulfonic acid phenyl ester;

4- [1- (2,4-dichloro-phenyl) -5- (2-hydroxy-cyclohexyl) -3-methyl-4-oxo-4,5-dihydro-1H-pyrrolo [3,2-c] pyridin 3,3,3-trifluoropropane-1-sulfonic acid -2-yl] phenyl ester;

4- [1- (2-chloro-phenyl) -5-cyclohexyl-3-hydroxymethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-yl ] 3,3,3-trifluoropropane-1-sulfonic acid phenyl ester;

Acid 4- [1- (2-chlorophenyl) -5-cycloexyl-3-hydroxymethyl-4-oxo-4,5-dihydro-1H-pyrrolo [3,2-c] pyridin-2-yl] phenyl ester 3,3-trifluoropropane-1-sulfonic;

4- [1- (2-chlorophenyl) -5- (2-hydroxycycloexyl) -3-hydroxymethyl-4-oxo-4,5-dihydro-1H-pyrrolo [3,2-c] pyridin-2-yl] phenyl 3,3,3-trifluoropropane-1-sulfonic acid ester;

4- (3-methyl-4-oxo-5-piperidin-1-yl-tolyl-4,5,6,7-tetrahydro-β-pyrrolo [3,2-c] pyridin-2-yl) phenyl 3,3,3-trifluoropropane-1-sulfonic acid ester;

1- (2,4-dichlorophenyl) -3-methyl-5-piperidin-1-yl-2- [4- (4,4,4-trifluoro-butoxy) phenyl] -1,5,6,7-tetrahydro -pyrrolo [3,2-c] pyridin-4-one;

as well as pharmaceutically acceptable salts thereof.

Preparation Methods

Compounds of formula I wherein R1, R2, R3, η and R4 are as previously defined may be prepared by reacting a compound of formula II

Copy formula on p.

wherein R2, R3, R4 and η are as previously defined as a common compound of formula III

R1X III

wherein R1 is as previously defined and X represents a leaving group, for example chlorine, bromine or iodine, in an inert solvent, for example dichloromethane or acetone, in the presence of a base, e.g. triethylamine, pyridine, 4-dimethylaminopyridine or depotassium carbonate, at a temperature in the range of -25 ° C to 150 ° C. The compounds of formula II may be prepared as summarized in General Synthesis 1 and 2. Certain compounds of formula II are believed to be novel and are claimed as part of the present invention.

Pharmaceutical Preparations

The compounds of the present invention will normally be administered orally, parenterally, intravenously, intramuscularly, subcutaneously or otherwise injectable, buccal, rectally, vaginally, transdermally, and / or nasally / or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a salt. pharmaceutically acceptable addition in a pharmaceutically acceptable dosage form. Depending on the patient disorder to be treated and the route of administration, the compositions may be administered at varying doses.

Suitably, the daily doses of the compounds of the present invention in the therapeutic treatment of humans are about 0.001-10mg / kg body weight, preferably 0.01-1mg / kg body weight. Oral formulations are preferred, particularly tablets or capsules, which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range 0.5 mg to 500 mg, for example 1 mg, 3 mg, 5 mg, 10 mg, mg, 50 mg, 100 mg and 250 mg.

According to another aspect of the invention there is also provided a pharmaceutical formulation comprising any of the compounds of the present invention or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable adjuvants, diluents and or carriers.

Pharmacological properties

The compounds of formula (I) are usable for treating obesity or overweight (e.g., promoting weight loss and maintaining weight loss), preventing weight gain (e.g., drug-induced or subsequent smoking cessation), for modulation of appetite and / or satiety, eating disorders (eg, insatiable appetite, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non-food items). essential), for the treatment of psychiatric disorders, such as psychotic and / or dohumor disorders, schizophrenia and schizo-affective disorder, bipolar disorders, anxiety, anxiety-depressive disorders. depression, mania, compulsive obsessive disorders, impulse control disorders (eg Gilles de la Tourette syndrome), attention disorders such as ADD / ADHD, stress and neurological disorders such as dementia, and cognitive and / or memory dysfunction (ρ. amnesia, Alzheimer's disease, Pick's dementia, aging dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild aging dementia), neurological and / or neurodegenerative disorders (eg, Multiple Sclerosis , Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelination-related disorders, neuroinflammatory disorders (eg Guillain-Barré syndrome).

The compounds are also potentially useful for the prevention or treatment of addiction and addiction disorders and behaviors (eg, alcohol and / or drug abuse, pathological gambling addiction, kleptomania), drug withdrawal disorders (e.g. , alcohol withdrawal with no perceptual disturbance; alcohol withdrawal delirium; deanfetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal .with or without perceptual disturbances; sedative withdrawal delirium, hypnotic or anxiolytic; withdrawal symptoms due to other substances), alcohol / drug-induced mood, anxiety and / or sleep disorders, beginning during withdrawal, and alcohol and / or drug withdrawal.

The compounds are also potentially useful for the prevention or treatment of neurological disorders such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal cord injury, neuropathy, migraine, vigilance disorders, sleep disorders (eg, architecture). disturbed sleep, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, head trauma.

The compounds are also potentially useful for the treatment of immune and cardiovascular disorders (eg, atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, stroke, cerebral infarction, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, metabolic disorders (eg conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesteroloemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, glycemic tolerance if impaired, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity-hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low and / or low HDL cholesterol levels. Elevated LDL, low deadiponectin levels), reproductive and endocrine disorders (p. eg treatment of hypogonadism in men, treatment of infertility or contraception, menstrual abnormalities / emenopathy, ovarianapolicistic disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH-deficient individuals, hirsutism in women, normal short stature) and related diseases with respiratory (eg asthma and chronic obstructive pulmonary disease) and gastrointestinal (eg, gastrointestinal motility dysfunction or intestinal propulsion systems, diarrhea, emesis, nausea, gallbladder disease, collectitis, gastroesophageal reflux disease) with obesity, ulcers).

The compounds are also potentially useful as agents in the treatment of dermatological disorders, cancers (eg, colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome. Turner's syndrome, Dehlhl's syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disorders (eg, deforming arthritis, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders. The compounds are also potentially useful as agents in the treatment of (esophageal) achalasia.

In another aspect, the present invention provides a compound of formula I as defined above for use as a medicament.

In another aspect, the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of obesity or overweight (e.g., promotion of weight loss and maintenance of weight loss), prevention weight gain (eg, medication-induced or subsequent to smoking cessation), appetite and / or satiety parameters, eating disorders (eg, inactivated appetite, anorexia, bulimia and compulsiveness), cravings (eg drugs, tobacco, alcohol, any epithelial macronutrients or non-essential food items) for the treatment of psychiatric disorders such as psychotic and / or mood disorders, schizophrenia and schizo-affective disorder, bipolar disorders, impulse control disorders (eg , Gilles de IaTourette syndrome), attention disorders such as ADD / ADHD, stress and neurological disorders such as dementia and cognitive and / or memory dysfunction (eg amnesia, Alzheimer's er, Pick's dementia, aging dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline and mild aging dementia), neurological and / or neurodegenerative disorders (e.g. Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelination-related disorders, neuroinflammatory disorders (eg Guillain-Barré syndrome).

In another aspect, the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of addiction and addiction disorders and behaviors (e.g., alcohol and / or drug abuse, gambling addiction). pathology, kleptomania), drug withdrawal disorders (eg, alcohol withdrawal with or without perceptual disturbance; delirium of alcohol withdrawal; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; withdrawal, hypnotic withdrawal) or anxiolytic, with or without perceptual disturbances; delirium from hypnotic or anxiolytic withdrawal; and withdrawal symptoms due to other substances), alcohol and / or drug-induced mood, anxiety and / or sleep disorder starting during withdrawal, relapse of alcohol and / or drug.

In another aspect, the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of neurological disorders such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal cord injury, neuropathy, migraine, surveillance disorder, sleep disorders (eg, disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, head trauma.

In another aspect, the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of immune cardiovascular disorders (e.g., atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms and arrhythmias, heart failure). congestive heart disease, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, stroke, cerebral infarction, ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, metabolic disorders (eg, conditions with reduced metabolic activity or a decrease in resting energy expenditure, such as a percentage of total fat free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercoleste rolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity-hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type diabetes II, low HLD and / or high LDL cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (p. eg treatment of hypogonadism in men, treatment of infertility or contraception, menstrual abnormalities / emeniopathy, ovarianapolicistic disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH deficient individuals, hirsutism in women, normal short stature) and related diseases with respiratory (eg, asthma and chronic obstructive pulmonary disease) and gastrointestinal (eg, gastrointestinal motility dysfunction or intestinal propulsion systems, diarrhea, emesis, nausea, gallbladder disease, coleticiasis, gastroesophageal reflux related to obesity, ulcers).

In another aspect, the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of dermatological disorders, cancers (e.g., colon, rectum, prostate, breast, ovary, endometrium, cervix). , gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Fohlich's syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disorders (eg, deforming arthritis, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders.

In yet another aspect, the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of obesity or overweight (e.g., promotion of weight loss and maintenance). weight loss), prevention of weight gain (eg, drug induced or subsequent to smoking cessation), for appetite and / or satiety modulation, eating disorders (eg, insatiable appetite, anorexia, bulimia cravings), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non-essential food items), for the treatment of psychiatric disorders such as psychotic and / or mood disorders, schizophrenia and schizo-affective disorder, bipolar disorders, anxiety, anxiety-depressive disorders. depression, mania, obsessive compulsive disorders, impulse control disorders (eg Gilles de la Tourette syndrome), attention disorders such as ADD / ADHD, stress and neurological disorders such as dementia, cognitive impairment and / or memory ( eg amnesia, Alzheimer's disease, Pick's dementia, aging dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline, mild aging edema), neurological and / or neurodegenerative disorders (eg Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelination-related disorders, neuroinflammatory disorders (eg, Guillain-Barré syndrome).

In yet another aspect, the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of addiction and disorders and behavior due to abuse (e.g., alcohol abuse and / or or drug, pathological gambling addiction, kleptomania), drug withdrawal disorders (eg, alcohol withdrawal with daring perceptual disorders; alcohol withdrawal delirium; deanfetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal ; sedative, hypnotic, or anxiolytic withdrawal, with or without perceptual disturbances; hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), alcohol and / or drug-induced mood, onset anxiety and / or sleep disorder during withdrawal, relapse of alcohol and / or drug.

In yet another aspect, the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for prophylaxis or treatment of neurological disorders such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal cord injury, neuropathy, migraine, surveillance disorders, sleep disorders (eg, disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, head trauma.

In yet another embodiment, the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of immune cardiovascular disorders (e.g., atherosclerosis, arteriosclerosis. of the chest, abnormal heart rhythms and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke , stroke, cerebral infarction, cerebral ischemia, thrombosecerebral, cerebral embolism, cerebral hemorrhage, metabolic disorders (eg, conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage). total fat free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, insulin resistance syndrome, metabolic syndrome, syndromeX syndrome obesity-hypoventilation (Pickwickian syndrome), type I diabetes, type II diabetes, low and / or elevated LDL cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (p. treatment of hypogonadism in men, treatment of infertility or as a contraceptive, menstrual abnormalities / emeniopathy, polycystic variant disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH-deficient individuals, hirsutism in women, normal low variant stature) and respiratory system-related diseases (eg, asthma and chronic obstructive pulmonary disease) and gastrointestinal (eg, gastrointestinal motility dysfunction or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, coleticiasis, gastric reflux) -esophageal related to obesity, ulcers).

In yet another aspect, the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the treatment or treatment of dermatological disorders, cancers (e.g., colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, dutobiliar), craniofringioma, Prader-Willi syndrome, Turner syndrome, Frohlich syndrome, glaucoma, infectious diseases, tractourinary disorders and inflammatory disorders (eg, deforming arthritis, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders.

The compounds of the present invention are particularly suitable for the treatment of obesity or overweight (e.g., promotion of weight loss and maintenance of weight loss), prevention or reversal of weight gain (e.g., rebound, induced by medication or subsequent smoking cessation), for appetite and / or satiety modulation, eating disorders (eg, insatiable appetite, anorexia, ecompulsive bulimia), cravings (for drugs, tobacco, alcohol, any appetite macronutrients or food items not essential).

The compounds of formula (!) Are useful for treating obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxiety depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia. , attention disorders such as ADHD, epilepsy and related conditions, and neurological disorders such as dementia, neurological disorders (eg, Multiple Sclerosis), Raynaud's syndrome, Parkinson's disease, Huntington's chorea, and Alzheimer's disease. The compounds are also potentially useful for the treatment of immune, cardiovascular, reproductive and endocrine disorders, shock shock and diseases related to the respiratory and gastrointestinal systems (eg diarrhea). The compounds are also potentially useful as agents in the treatment of indications of prolonged abuse, addiction and / or relapse, e.g. eg withdrawal symptoms from treatment drug (nicotine, ethanol, cocaine, opiates etc.), addiction and / or treatment drug (nicotine, ethanol. cocaine, opiates etc.). The compounds may also eliminate weight gain which usually accompanies smoking cessation.

In another aspect, the present invention provides a compound of formula I as previously defined for use as a medicament.

In yet another aspect, the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, depressive disorders, depression, cognitive disorders. , memory disorders, obsessive-compulsive disorders, // anorexia, bulimia, attention disorders such as ADHD, epilepsy and related conditions, neurological disorders such as dementia, neurological disorders (eg, Multiple Sclerosis), Parkinson's disease, Huntington's chorea and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (eg diarrhea) and indications of prolonged abuse, addiction and / or relapse, e.g. eg symptoms of treatment drug addiction (nicotine, ethanol, cocaine, opiates etc.) and / or treatment drug withdrawal (nicotine, ethanol, cocaine, opiates etc.).

In yet another aspect, the present invention provides a method for treating obesity, psychiatric disorders such as psychotic disorders such as schizophrenia and bipolar disorders, anxiety, anxiety depressive disorders, depression, cognitive disorders, memory disorders, obsessive compulsive disorders, anorexia, bulimia, attention disorders such as ADHD, epilepsy and related conditions, neurological disorders such as dementia, neurological disorders (eg, Multiple Sclerosis), Parkinson's disease, Huntington's chorea and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, shocks , diseases related to the respiratory and gastrointestinal systems (eg diarrhea) and indications of prolonged abuse, addiction and / or relapse, e.g. symptoms of treatment drug dependence (nicotine, ethanol, cocaine, opiates etc.) and / or treatment drug withdrawal (nicotine, ethanol, cocaine, opiates etc.), comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need of it.

The compounds of the present invention are particularly suitable for the treatment of obesity, e.g. eg, by reducing appetite and body weight, maintaining weight reduction and preventing bounce.

The compounds of the present invention may also be used to prevent or reverse medication-induced weight gain, e.g. eg, weight gain caused by antipsychotic (neuroleptic) treatment (s). The compounds of the present invention may also be used to avoid altering the weight gain associated with smoking cessation.

The compounds of the present invention are suitable for use in treating the above indications in juvenile or adolescent patient populations.

The compounds of the present invention may also be suitable for use in regulating bone mass and bone loss and therefore useful in treating osteoporosis and other bone diseases.

The compounds of the present invention may also be used in the treatment of liver disease, for example liver fibrosis, cirrhoealcoholic liver liver disease, chronic viral hepatitis, alcoholic stearate or liver cancer.

Combination Therapy

The compounds of the present invention may be combined with another therapeutic acid which is useful in the treatment of obesity, such as other anti-obesity drugs, which affect energy expenditure, glycolysis, gluconeogenesis, phylogenolysis, lipolysis, lipogenesis, fat absorption, fat storage. , excretion of fat at a pH to a pH of anxiety, appetite / motivation, food intake, or GI motility.

The compounds of the present invention may further be combined with another therapeutic agent which is useful in the treatment of obesity-associated disorders such as hypertension, hyperlipidemias, dyslipidemias, diabetes, sleep apnea, asthma, cardiac disorders, atherosclerosis, macrobascular diseases, steatosis. liver, cancer, joint disorders and gallbladder disorders. For example, a compound of the present invention may be used in combination with another therapeutic agent that lowers blood pressure or that decreases the LDL: HDL ratio or an agent that causes a decrease in circulating LDL-cholesterol levels. In patients with diabetes mellitus, the compounds of the present invention may also be combined with therapeutic agents used to treat microangiopathic complications. The compounds of the present invention may be used alongside other therapies for the treatment of obesity and its associated complications, metabolic syndrome. and type 2 diabetes, these including drugs debiguanide, insulin (synthetic insulin analogues) and oral antihyperglycemic drugs (these are divided into prandial glucose regulators and daalphaglycosidase inhibitors).

In another aspect of the invention, the compound of formula I or a pharmaceutically acceptable salt thereof may be administered in combination with a PPAR modulating agent. PPAR modulating agents include but are not limited to a PPAR alpha and / or gamma agonist or pharmaceutically acceptable salts thereof, solvates, solvates of such salts or prodrugs. Suitable PPAR alpha and / or gamma agonists, their salts, solvates of such salts or pharmaceutically acceptable prodrugs are well known in the art.

In addition, the combination of the invention may be used in conjunction with a sulfonylurea. The present invention also includes a compound of the present invention in combination with a cholesterol lowering agent. Cholesterol lowering agents referred to in this application include but are not limited to HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) inhibitors. Suitably, the inhibitor of HMG-CoA reductase is a statin.

In the present application, the term "cholesterol lowering agent" also includes chemical modifications of HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.

The present invention also includes a compound of the present invention in combination with an ileal acid transport system inhibitor (IBAT inhibitor). The present invention also includes a compound of the present invention in combination with an acidobiliary bonding resin.

The present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or colestagel.

According to a further further aspect of the present invention, a combination treatment is provided comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier with simultaneous administration. sequentially or separately from one or more of the following agents selected from:

a CETP (cholesterylester transfer protein) inhibitor;

a cholesterol absorption antagonist;

an MTP (microsomal transfer protein) inhibitor;

a nicotinic acid derivative including slow release and combination products;

a phytosterol compound: probucol;

an anticoagulant, an omega-3 fatty acid;

another anti-obesity compound, for example sibutramine, phentermine, orlistat, bupropion, ephedrine, thyroxine;

a hypertensive compound, for example an angiotensin-converting enzyme (ACE) inhibitor, a daangiotensin II receptor antagonist, an adrenergic blocker, an alpha adrenergic blocker, a beta adrenergic blocker, a mixed alpha / beta adrenergic blocker, an adrenergic stimulant, calcium channel blocker, an AT-1 blocker, a saluretic, a diuretic or a vasodilator;

a melanin concentrating hormone (MCH) modulator, an NPY receptor modulator, an orexin receptor modulator;

a phosphoinositide-dependent protein kinase modulator

(PDK); or

nuclear receptor modulators, for example, LXR, FXR, RXR, GR, ERRa, β, PPARa, β, γ and RORalfa;

a monoamine transmission modulating agent, for example a selective serotonin reuptake inhibitor (SSRI), a norepinephrine reuptake inhibitor (NARI), a norepinephrine serotonin reuptake inhibitor (SNRI), a monoamine oxidase inhibitor (MAOI), a tricyclic antidepressant agent (TCA), a noradrenergic and specific adrenergic antidepressant (NaSSA);

an antipsychotic agent, for example olanzapine and clozapine; a serotonin receptor modulator; a leptin / leptin receptor modulator; a ghrelin / ghrelin receptor modulator; a DPP-IV inhibitor;

or a salt, solvate, solvate of such a salt or prodrug pharmaceutically acceptable thereof, optionally together with a pharmaceutically acceptable diluent or carrier, to a warm blooded animal such as man in need of such therapeutic treatment.

According to another additional aspect of the present invention, a combination treatment is provided comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier with simultaneous, sequential administration. or separate from very low calorie diets (VLCD) or low calorie diets (LCD).

Therefore, in a further aspect of the invention there is provided a method for treating obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment, comprising administering to said animal an effective amount of a compound of formula. I or a pharmaceutically acceptable salt thereof is simultaneous, sequential or separate administration with an effective amount of a compound of one of the other classes of compounds described in this combination section, or a salt, solvate, solvate thereof or a pharmaceutically acceptable salt thereof.

Therefore, in a further aspect of the invention there is provided a method for treating hyperlipidemic conditions in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula I or a salt thereof. pharmaceutically acceptable, in simultaneous, sequential or separate administration, with an effective amount of a compound of one of the other classes of compounds described in this combination section or a salt, solvate, solvate of such salt or prodrug-pharmaceutically acceptable thereof.

According to another aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a compound of one of the other classes of compounds described in this combination section or a salt, solvate, solvate of such salt. or a pharmaceutically acceptable prodrug thereof, in combination with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provided a kit comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a compound of one of the other decomposed classes described in this combination section or a salt, solvate, solvate, detail salt or propylate. pharmaceutically acceptable drug thereof.

According to a further aspect of the present invention, there is provided a kit comprising:

(a) a compound of formula I or a pharmaceutically acceptable salt thereof in a first unit dosage form;

b) a compound of one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug thereof; in a second form unit fingering; and

c) container device for containing said first and second dosage forms.

According to another aspect of the present invention there is provided a kit comprising:

a) a compound of formula I or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form;

b) a compound of one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug thereof, in a second unitary form; and

c) container device for containing said first and second dosage forms.

According to another aspect of the invention there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof and one of the other compounds described in this combination section, or a salt, solvate, solvate of such pharmaceutically acceptable salt or prodrug thereof. , in the manufacture of a drug for use in the treatment of obesity and its associated complications in a warm-blooded animal such as man.

According to another aspect of the invention there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof and one of the other compounds described in this combination section or a salt, solvate, solvate of such a pharmaceutically acceptable salt or prodrug thereof. , in the manufacture of a drug for use in the treatment of hyperlipidemic conditions in a warm-blooded animal such as man.

According to another aspect of the present invention there is provided a combination treatment comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with simultaneous, sequential or separated from an effective amount of one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, to a blood animal such as man in need of therapeutic treatment.

In addition, a compound of the present invention may also be combined with therapeutic agents which are useful in the treatment of disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, untreated steatoepatitis). alcohol, osteoarthritis and some cancers) and psychiatric and neurological conditions.

It should be understood that there are medically accepted definitions of obesity and overweight. A patient can be identified, for example, by measuring body mass index (BMI), which is calculated by dividing the weight in kilograms by height in square meters and comparing the result with the definitions.

When the compounds of formula I are useful in causing smoking cessation, preventing weight gain from smoking cessation, treating nicotine withdrawal and avoiding nicotine dependence, they may also be combined with other compounds known to have one or more of these effects. , for example, nicotine, a danicotin agonist or partial agonist, a monoamine oxidase inhibitor or antidepressants such as buupropion, doxepine, nortriptyline or an anxiolytic such as buspirone or clonidine.

Pharmacological Activity

The compounds of the present invention are active against the CB1 gene receptor product. The affinity of the compounds of the present invention for central cannabinoid receptors is demonstrable in the methods described in Devane et al., Molecular Pharmacology, 1988, 34,605 or those described in WO 01/70700 or EP 656354. Alternatively, the assay may be performed as follows:

10 μg of membranes prepared from cells stably transfected with the CBl gene were suspended in 100 μΐ of 100 mM NaCl, 5 mM MgC12, 1 mM EDTA, 50 mM HEPES (pH 7.4), 1 mM DTT, 0.1% BSA and 100 μηι GDP. To this was added a deagonistic EC80 concentration (CP55940), the required concentration of the test compound and 0.1 μCi [35S] -GTPyS. The reaction was allowed to proceed at 30 ° C for 45 min. The samples were then transferred to GF / B filters using a cell harvester and washed with wash buffer (50 mM Tris (pH 7.4), 5 mM MgCl2, 50 mM NaCl). The filters were then covered with scintillant and counted with the amount of [S] -GTPyS retained by the filter.

Activity is measured in the absence of all ligands (minimum activity) or in the presence of an EC80 concentration of CP55940 (maximum activity). These activities are set to 0% and 100% reactivity respectively. At various concentrations of the new ligand, activity is calculated as a percentage of the maximum activity and plotted. Data are adjusted using the equation y = A + ((BA) / l + ((C / x) UD)) and the value IC50 determined as the concentration required to provide semi-maximal inhibition of GTPγS binding under the conditions used. The compounds of the present invention are active at the receptor CB1 (IC50 <1 micromolar). Most preferred compounds have IC 50 <200 nanomolar. For example, Example 1 has an IC50 of 0.98 nM.

The compounds of the present invention are believed to be selective CB1 sereagonists or inverse agonists. The potency, inelectivity profile and side effect propensity may limit the usefulness of previously known compound clicates with alleged CB1 antagonistic / inverse agonistic properties. In this regard, preclinical evaluation of the compounds of the present invention in gastrointestinal and / or cardiovascular function models indicates that they offer significant advantages over representative reference CB1 antagonist / inverse agonist agents.

The compounds of the present invention may provide additional benefits in terms of potency, selectivity profile, bioavailability, plasma half-life, blood brain permeability, protein binding (e.g., higher free drug fraction) or plasma solubility, in comparison. with the representative CB1 antagonist / inverse agonist agents of reference.

The compounds of the present invention have improved solubility in organic solvents compared to the above compounds. For example, Example 19 of WO 03/027114 (2- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -3-methyl-5- (1-piperidinyl) -1,5,6,7- tetrahydro-4H-pyrrolo [3,2-c] pyridin-4-one) was found to be insoluble in dimethyl sulfoxide, while the compounds of the present invention were all soluble in dimethyl sulfoxide. This increase in solubility in organic solvents would be expected to result in improvements in availability and ease of manufacture and formulation.

The usefulness of the compounds of the present invention in treating obesity and related conditions is demonstrated by a decrease in body fat in restaurant diet-induced obese mice. Female C57B1 / 6J mice were given ad libitum access to a high-calorie (soft chocolate / chocolate, cheesy and nugá) pastry diet and standard Iab food for 8-10 weeks. The composts to be tested were then administered systemically (iv, ip, sc or po) once daily for a minimum of 5 days and the body weights of mice monitored on a daily basis. Simultaneous assessment of body fatality was performed by DEXA imaging at baseline and study termination. Blood sampling was also performed to test changes in obesity-related plasma markers. The compounds of the present invention show superior weight reduction compared to the prior art compounds.

Examples

Abbreviations

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinoneDME dimethoxyethane

Dimethylformamide DMF

EtOAc ethyl acetate

NBS N-Bromosuccinimide

Methanol MeOH

p-TSA toluenesulfonic acid

it's room temperature

TBAF Tetrabutylammonium Fluoride

TEA triethylamine

THF tetrahydrofuran

triplet t

s singlet

d doublet

q quartetquint quintet multiplet

br broad

bs broad singlet

dm broad triple multipletobt doublet

dd doublet of doublet

General Experimental Procedures

Mass spectra were recorded on a Micromass ZQ single quadripolar mass spectrometer or a Micromass LCZ single quadripolar mass spectrometer, both equipped with a pneumatically assisted electrospray interface (LC-MS). 1 H-NMR measurements were performed on a Varian Mercury 300 or a Varian Inova 500, operating at 1 H frequencies of 300 and 500 MHz5 respectively. Chemical changes are given in ppm with CD13 as internal standard. CDCl3 is used as an NMR5 solvent unless otherwise noted. Purification was performed on a semi-preparative HPLC (High Performance Liquid Chromatography) with a mass-driven fractional collector, Shimadzu QP 8000 single quadripolar mass spectrometer, equipped with a C819 χ 100 mm column. The mobile phase used was, if nothing else mentioned, acetonitrile buffer (0.1 M ammonium acetate: acetonitrile 95: 5).

Example 1

4- [1- (2-chlorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine-2 -yl] phenyl 3,3,3-Trifluoropropane-1-sulfonic acid ester

Step 1 - 3- (Piperidin-I-ylamino) propionic acid methyl ester

In a solution of 1-aminopiperidine (100 g, 1.00 mol) in dry methanol at 0 ° C, methyl acrylate (99.0 ml, 1.10 mol) was added in stock. The resulting mixture was stirred at room temperature for night. After evaporation of the solvent, heptane was added to the residue and the white solid (impurity) filtered off. The filtrate was concentrated to dryness to afford 80.0 g (43%) of the title compound as a yellow oil.

Step 2 - N- (2-Methoxycarbonylethyl) -N-piperidin-1-yl-maloamic acid ethyl ester

To a solution of 3- (piperidin-1-ylamino) propionic acid methyl ester (80.0 g, 0.43 mol) in dichloromethane was added triethylamine (71.0 ml, 0.50 mol) followed by the slow addition of chloride. of ethylmalonyl (60.0 ml, 0.47 mol) at 0 ° C. The resulting slurry was stirred in

room temperature for 4 hours. Water was added and the phases separated. The organic phase was dried (Na 2 SO 4), filtered and concentrated. Flash vapor chromatography (toluene: EtOAc 9: 1-1: 1) provided 81.0 g (63%) of the product as a waste oil without further purification.

Step 3 - 2,4-Dioxo- [1,1'] bipiperidinyl-3-acid ethyl ester

carboxylic

In a solution of N- (2-methoxycarbonylethyl) -N-piperidin-1-yl-maloamic acid ethyl ester (60.0 g, 0.20 mol) in a mixture of THF (1100 mL) and DMF (490 mL) Cesium carbonate (195 g, 0.60 mol) was added. The resulting mixture was boiled under reflux (80 ° C) for 48 hours. The cooled reaction mixture was filtered and the filtrate evaporated. The combined filtered solid and the filtered residue were purified by flash chromatography (70: 30 CH 2 Cl 2: MeOH) to provide 15.0 g (28%) of the title compound as a pale yellow oil.

Step 4 - [1,1 '] Bipiperidinyl-2,4-dione

The oil from Step 3 was dissolved in 10% acetic acid (250ml) and the solution boiled under reflux for one hour. The cooled reaction mixture was evaporated and the residue purified by flash chromatography (9: 1-1: 1 CH 2 Cl 2: acetone) to afford 4.00 g (36%) of the title compound as a semi-solid.

Step 5- 1- (2-Chlorophenylamino) -propan-2-one

A mixture of 2-chloroaniline (13.2 ml, 0.125 mol), iodoacetone (26.6 g, 0.145 mol) and potassium carbonate (18.1 g, 0.13 mol) in DMF (200 ml) was heated under nitrogen. IOO0C at night. After cooling to rt, water was added and the mixture extracted with ether (x3). The combined organic extracts were washed with water, dried (Na2 SO4), filtered and concentrated. Flash chromatography (Heptane: EtOAc80: 20) afforded 16.0 g (70%) of the title compound as a brown liquid.

Step 6- 1- (2-Chlorophenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3,2-c] pyridine-4-one

In a solution of [1, r] bipiperidinyl-2,4-dione from Step 4 (2.49 g, 12.7 mmol) in dry toluene (240 mL) at room temperature was added 1- (2-chlorophenylamino) propan-2-one (2.33 mg, 12.7 mmol) from Step 5 followed by a catalytic amount of p-TSA. The reaction mixture was boiled under reflux with a Dean-Stark collector, and 90ml of toluene was collected in the collector. Then 1 molar equivalent dep-TSA was added and the reaction mixture was boiled overflow overnight. After cooling to room temperature, the reaction mixture was evaporated and purified by flash chromatography (heptane: EtOAc gradient) to provide 0.93 g (21%) of the title compound.

Step 7 - 2-Bromo-1- (2-chlorophenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3,2-c] pyridine-4-one

<formula> formula see original document page 33 </formula>

In a solution of 1- (2-chlorophenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3,2-c] pyridine-4-one (O, 93 g, 2.70 mmol) in DMF (30 mL) was added NBS (0.50, 2.84 mmol) at 0 ° C. The reaction mixture was stirred at this temperature for one hour, and then water was added. The mixture was extracted with ether (x3). The combined ether extracts were dried (Na 2 SO 4), filtered and concentrated to provide 0.92 g (84%) of the title compound after flash chromatography (heptane: EtOAc gradient).

Step 8 - 1- (2-Chlorophenyl) -2- (4-hydroxyphenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydro-pinOlo [3,2-c] pyridine -4-one

2-Bromo-1- (2-chlorophenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3,2-c] pyridine-4-one (O, 92 g, 2.25 mmol), 4-hydroxyphenylboronic acid (0.35 g, 2.50 mmol) and tetracis (triphenylphosphino) palladium (O) (350 mg) were dissolved in DME (46 ml) and 1 M Na 2 CO 3 ( 12 ml)). The resulting solution was degassed and heated to 60 ° C under nitrogen overnight. Water and EtOAc were added after cooling and the aqueous phase extracted with EtOAc (x3). The combined organic extracts were dried (Na 2 SO 4), filtered and concentrated to afford a crude product which was purified by flash chromatography (heptane: EtOAc gradient) to afford 0.54 g (55%) of the product as a pale yellow solid.

Step 9 - 4- [1- (2-chlorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] 3,3,3-Trifluoropropane-1-sulfonic acid pyridin-2-yl] phenyl ester

In a solution of 1- (2-chlorophenyl) -2- (4-hydroxyphenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3,2-c] pyridine-2-one 4-one (0.54 g, 1.24 mmol) in dichloromethane (30 mL) at 0 ° C was added triethylamine (0.20 mL, 1.50 mmol) followed by 3,3,3-trifluoropropane sulfonyl chloride (295 mg 1.50 mmol). The reaction mixture was subsequently stirred at room temperature for 2.5 hours. Concentration and purification by flash vapor chromatography (heptane: EtOAc gradient) afforded 65 mg (9%) of the title compound as a colorless solid. 1 H NMR (CDCl 3): δ 7.57-7.08 (8Η, m), 3 , 78-3.71 (2Η, m), 3.50-3.44 (2Η, m), 3.40-3.00 (2Η, broad), 2.85-2.65 (4Η, m) 2.41 (3H, s), 1.80-1.50 (6H, m), 1.40-1.20 (2H, m). MS: 596 (M + H). HPLC: 93%

Example 2

4- [1- (2,4-dichlorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine 3,3,3-Trifluoropropane-1-sulfonic acid -2-yl] phenyl ester

<formula> formula see original document page 35 </formula>

Step 1- 1- (2,4-Dichlorophenylamino) propan-2-one A mixture of 2,4-dichloroaniline (20.2 g, 0.125 mol), iodoacetone (26.6 g, 0.145 mol) and potassium carbonate (18 0.1 g) in DMF (200 ml) was heated under nitrogen at 100 ° C overnight. After cooling to rt, water was added and the mixture extracted with ether (x3). The combined organic extracts were washed with water, dried (Na 2 SO 4), filtered and concentrated. Flash chromatography (Heptane: EtOAc 90: 10 - 80: 20) afforded 13.6 g (50%) of the title compound as a brown solid.

Step 2- 1- (2,4-Dichlorophenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3,2-c] pyridine-4-one

To a solution of [1,1'] bipiperidinyl-2,4-dione (520 mg, 2.65 mmol) of Example 1 Step 4 in dry toluene (25 ml) at room temperature was added 1- (2,4-dichlorophenylamino) -propan-2-one (576 mg, 2.64 mmol) from Step 1 above followed by a catalytic amount of p-TSA. The reaction mixture was boiled under reflux with a Dean-Stark collector, and 10 ml of toluene was collected in the collector. A molar equivalent of p-TSA (250 mg) was added and the reaction mixture boiled under reflux for 5.5 hours. After cooling to room temperature, the reaction mixture was evaporated and purified by flash chromatography (heptane: EtOAc gradient) to afford 250 mg (25%) of the title compound as a brown solid. A trial run with 1.51 g 1- (2,4-dichlorophenylamino) propan-2-one provided 0.68 g (26%) of the product.

Step 3- 2-Bromo-1- (2,4-Dichlorophenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3,2-c] pyridine-4 -ona

In a solution of 1- (2,4-dichlorophenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3,2-c] pyridine-4-one (0, 93 g, 2.46 mmol) in DMF (25 mL) was added NBS (0.48, 2.71 mmol) at 0 ° C. The reaction mixture was stirred at this temperature for one hour and then water was added. The mixture was extracted with ether (x3). The combined ether extracts were dried (Na2 SO4), filtered and concentrated to provide 0.45 g (40%) of the title compound after flash chromatography (heptane: EtOAc gradient).

Step 4- 1- (2,4-Dichlorophenyl) -2- (4-hydroxyphenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3,2-c ] pyridine-4-one

2-Bromo-1- (2,4-Dichlorophenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3,2-c] pyridine-4-one (450 mg 0.98 mmol), 4-hydroxyphenylboronic acid (150 mg, 1.09 mmol) and tetracis (triphenylphosphino) palladium (O) (150 mg) were dissolved in DME (20 mL) and 1 M Na 2 CO 3 (5 mL)). The resulting solution was degassed and heated to 60 ° C under nitrogen overnight. Water and EtOAc were added after cooling and the aqueous phase extracted with EtOAc (x3). The combined organic extracts were dried (Na2 SO4), filtered and concentrated to afford a crude product, which was purified by flash chromatography (heptane: EtOAc gradient) to afford 0.40 g (87%) of the product as a pale yellow solid.

Step 5- 4- [1- (2,4-dichlorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2- c] pyridin-2-yl] phenyl 3,3,3-trifluoropropane-1-sulfonic acid ester

In a solution of 1- (2,4-dichlorophenyl) -2- (4-hydroxyphenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3,2-c] pyridine-4-one (0.40 g, 0.85 mmol) in dichloromethane (20 mL) at 0 ° C was added triethylamine (0.14 mL, 1.02 mmol), followed by 3,3,3-chloride. trifluoropropanesulfonyl (0.20g, 1.02 mmol). The reaction mixture was subsequently stirred at room temperature for two hours. Concentration and purification by flash chromatography (heptane: EtOAc gradient) afforded 200 mg (37%) of the title compound as a colorless solid.

1H NMR (CDCl3): δ 7.51 (1H, m), 7.34-7.02 (6H, m), 3.75 (2H, m), 3.53-3.44 (3H, m) , 3.40-3.00 (2H, broad s), 2.87-2.60 (5H, m), 2.41 (3H, s), 1.80-1.50 (6H, m) 1.40-1.20 (2H, m). MS: 630 (M + H). HPLC: 95%

Example 3

4- [1- (2-chloro-4-fluorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5,6,7-tetrahydro-1H-pinOlo [3,2-c ] pyridin-2-yl] phenyl 3,3,3-Trifluoropropane-1-sulfonic acid ester Step 1- 4- (2-Chloro-4-fluorophenylamino) -5,6,3 ', 4', 5,, 6 '-

hexahydro-2'Η-Γ 1,1,1bipyridinyl-2-one

[1,1 '] -Bipiperidinyl-2,4-dione (2.00 g, 10.19 mmol) was dissolved in toluene (8 mL) and 2-chloro-4-fluorophenylamine (1.78 g, 12.23 mmol) has been added. More toluene (5 ml) was added. The reaction mixture was boiled under reflux at 100 ° C for 17 h then allowed to cool. When the reaction mixture reached rt, the product precipitated and was collected by filtration to yield a beige solid (1.80 g, 55%).

1H-NMR (400 MHz, CDCl3) δ 7.41-7.32 (1H, m), 7.18-7.09 (1H, m), 7.00-6.90 (1H, m), 5 , 51 (1H, s), 5.11 (1H, s), 3.54 (2H, t), 3.38-2.67 (4H, br), 2.57 (2H, t), 1, 74-1.50 (4H, m), 1.43-1.30 (2H, m).

Step 2 3- (2- (4- (tert-Butyldimethylsilanyloxy) phenyl-1-methyl-2-oxo-ethyl) -4- ('2-chloro-4-fluorophenylamino) -5.6.3', 4 ', 5, 6'-hexahydro-2'H-Γ1,1,1bipyridinyl-2-one

NaH (0.15 g, 6.25 mmol) was placed in a vial of nitrogen and dry THF (5 mL) was added. The mixture was cooled to 0 ° C with an ice bath and 4- (2-chloro-4-fluoro-phenylamino) -5,6,3 ', 4', 5 ', 6'-hexahydro-2'H- [1, r] bipyridinyl-2-one (0.70 g, 2.16 mmol) suspended in dry THF (8 mL) was added dropwise. After 1h 40 min detetrabutylammonium iodide (0.085 g, 0.23 mmol) was added followed by the addition of 2-bromo-1- [4- (tert-butyldimethylsilanyloxy) phenyl] propan-1-one (1.22 g, 3.27). mmol) dissolved in dry THF (2 mL). The ice bath was removed after the last addition. The reaction was continued at rt for 4 h, after which the gassing was quenched by the addition of pH 7.0 phosphate buffer. The THF was evaporated. DCM / water were added and the phases separated. DCM was evaporated from the dried organic layer to yield the crude product as an orange solid (1.135 g crude).

Step 3- 2- [4- (tert-Butyldimethylsilanyloxy) phenyl "1-1- (2-chloro-4-fluorophenyl) -3-methyl-5-piperidin-1-yl-1,5,6,4etrahydro-pyrrole3,2 -clpiridin-4-one

3- {2- [4- (tert-Butyldimethylsilanyloxy) phenyl] -1-methyl-2-oxo-ethyl} -4- (2-chloro-4-fluorophenylamino) -5,6,3 ', 4', 5 ', 6'-hexahydro-2'H- [1,1'] bipyridinyl-2-one (1.135 g, 1.94 mmol) was suspended in toluene (5 mL) and toluene-4-sulfonic acid (0.037 g, 0.19 mmol) was added. The reaction mixture was cooled in a microwave oven at 100 ° C for 30 min. Water / toluene was added to the reaction mixture and the separated phases. The organic phase was washed with water, dried (MgSO 4), filtered and evaporated to yield crude product (0.929 g crude).

Step 4- 1- (2-Chloro-4-fluoro-phenyl) -2- (4-hydroxy-phenyl-3-methyl-5-piperidin-1-yl-1,5,6,7 | "tetrahydropyrrolor") 2-clpyridin-4-one

2- [4- (tert-Butyldimethylsilanyloxy) phenyl] -1- (2-chloro-4-fluorophenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3.2 -c] pyridin-4-one (0.929 g, 1.63 mmol) was suspended in THF (10 mL) and TBAF (1 M in THF, 1.64 mL) was added. The reaction mixture was stirred at rt for 1h, after which time the solvent was evaporated and ethyl acetate / water added. The phases were separated and the organic phase dried and evaporated. The crude product was recrystallized from ethyl acetate / toluene to afford the product as an orange solid (0.223 g, 23% over 3 steps).

Step 5- 4- [1- (2-chloro-4-fluorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5,6,7-tetrahydro-1H-pyrrolo [3, 2-c] pyridin-2-yl] phenyl 3,3,3-trifluoropropane-1-sulfonic acid ester

1- (2-Chloro-4-fluorophenyl) -2- (4-hydroxyphenyl) -3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo [3,2-c] pyridin-2-one 4-one (0.223 g, 0.49 mmol) was co-concentrated with pyridine twice and placed under nitrogen. Pyridine (2.5 mL) was added and the reaction mixture cooled to 0 ° C with a flock of ice, followed by addition of 3,3-trifluoropropane-1-sulfonyl chloride (0.153 g, 0.78 mmol). The reaction mixture was cooled to 0 ° C in an ordinary ice bath, followed by the addition of 3,3,3-trifluoropropane-1-sulfonyl chloride (0.153 g, 0.78 mmol). The reaction mixture was stirred at 0 ° C for 3 h while adding more 3,3,3-trifluoropropane-1-sulfonyl chloride (0.171 g, 0.87 mmol) after 1 h 10 min. The ice bath was removed and the water mixture evaporated. The crude product was purified by HPLC to yield the product as a beige solid after freeze drying (0.19 g, 63%). HRMS Calc. for [C 28 H 28 ClF 4 N 3 Cl 2 H] +: 614.150. Found: 614.150.

1H-NMR (400 MHz, CD3OD) δ 7.33-7.25 (2H, m), 7.20-7.10 (4H, m), 7.08-7.01 (1H, m), 3 , 67-3.54 (4H, m), 3.10-2.67 (6H, m), 2.59 (2H, t), 2.22 (3H, s), 1.83-1.49 (4H, m), 1.49-1.19 (2H, m).

Example 4- 1- (2-Chlorophenyl-3-methyl-5-piperidin-1-yl-2-Γ4- (4,4,4-trifluorobutoxy) phenyl-1,5,6,7-tetrahydropyrrolor-3,2-cpyridine-4 -ona

Potassium carbonate (0.19 g, 1.38 mmol) was added in a solution of 1- (2-chlorophenyl) -2- (4-hydroxyphenyl) -3-methyl-5-piperidin-1-yl-1,5 Ex. 1, 6,7-Tetrahydropyrrolo [3,2-c] pyridine-4-one from Step 1 (0.50 g, 1.15 mmol) in DMF (30 mL) followed by 1-iodo-4,4 4,4-trifluorobutane (328 mg, 1.38 mmol). The reaction mixture was heated at 80 ° C overnight. TLC showed very little conversion to the starting material; 656 mg (2 eqv.) 1-iodo-4,4,4-trifluorobutane and 380 mg (2 eqv.) Of K 2 CO 3 were added and continued heating for one hour. After cooling to rt, water was added and the product extracted with EtOAc (x3). The combined organic extracts were washed with brine (x2), dried (Na2SO4), filtered and concentrated. Flash vapor chromatography (heptane: EtOAc gradient) afforded 250 mg (40%) of the title compound as a colorless solid.

1H NMR (CDCl3): δ 7.47 (1H, m), 7.34-7.18 (2H, m), 7.11-7.05 (3H, m), 6.74 3.75 (2H , m), 3.97 (2H, t), 3.73-3.70 (2H, broad t), 3.40-2.80 (4H, broad m), 2.74-2.61 (2H , m), 2.39-2.24 (5H, wk), 2.07-2.00 (2H, m), 1.69-1.61 (4H, m), 1.48-1.46 (2H, m). MS: 568 (M + Na). HPLC: 97.5%

The following compounds are prepared in a manner similar to those described above:

Example 5: 3,3,3 - 4- [1- (2-chlorophenyl) -5- (2-hydroxy-cyclohexyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H pyrrolo [3,2-c] pyridin-2-yl] phenyl trifluoropropane-1-sulfonic acid ester

Example 6: 4- [1- (2,4-dichlorophenyl) -5- (2-hydroxycycloexyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2- c] pyridin-2-yl] phenyl3,3,3-Trifluoropropane-1-sulfonic acid ester

Example 7: 4- [1- (2-chlorophenyl) -5- (3-hydroxy-cyclohexyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pinOlo [3,2- c] pyridin-2-yl] phenyl3,3-Trifluoropropane-1-sulfonic acid ester

Example 8: 4- [1- (2-Chloro-phenyl) -5-cyclohexyl-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pinOlo [3,2-c] pyridin-2-one 3,3,3-trifluoropropane-1-sulfonic acid 2-yl] phenyl ester

Example 9: 4- [1- (2,4-Dichlorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5-dihydro-1H-pyrrolo [3,2-c] pyridin-2-one 3,3,3-trifluoropropane-1-sulfonic acid 2-yl] phenyl ester

Example 10: 4- [1- (2,4-Dichlorophenyl) -5- (2-hydroxycyclohexyl) -3-methyl-4-oxo-4,5-dihydro-1H-pyrrolo [3,2-c] pyridin-2-one yl] phenyl 3,3,3-trifluoropropane-1-sulfonic acid ester

Example 11: 4- [1- (2-Chlorophenyl) -5-cyclohexyl-3-hydroxymethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrolo [3,2-c] pyridin-2-one 3,3,3-Trifluoropropane-1-sulfonic acid yl] phenyl ester

Example 12: 4- [1- (2-chlorophenyl) -5-cyclohexyl-3-hydroxymethyl-4-oxo-4,5-dihydro-1H-pinOlo [3,2-c] pyridin-2-yl] phenyl ester of 3,3,3-Trifluoropropane-I-sulfonic acid

Example 13: 4- [1- (2-chlorophenyl) -5- (2-hydroxy-cyclohexyl) -3-hydroxymethyl-4-oxo-4,5-dihydro-1H-pyrrolo [3,2-c] pyridin-2-one 2-yl] phenyl ester 3,3,3-Trifluoropropane-1-sulfonic acid

Example 14: 4- (3-Methyl-4-oxo-5-piperidin-1-yl-tolyl-4,5,6,7-tetrahydro-1H-pinOlo [3,2-c] pyridin-2-one il) plienyl 3,3,3-Trifluoropropane-1-sulfonic acid ester

Example 15: 1- (2,4-Dichloroplienyl) -3-methyl-5-piperidin-1-yl-2- [4- (4,4,4-trifluoro-butoxy) -phenyl] -1,5,6 , 7-tetrahydropyrrolo [3,2-c] pyridin-4-one.

It will be appreciated by those skilled in the art that the compounds of the present invention may be called as 1,5,6,6-tetrahydro-1H-pyrrolo [3,2-c] pyridines or may be called as 4,5,6,6,7 tetrahydro-1H-pyrrolo [3,2-c] pyridines. <formula> formula see original document page 42 </formula> General Synthetic Route 2

<formula> formula see original document page 43 </formula>

Claims (17)

A compound and pharmaceutically acceptable salts thereof, characterized in that it is of formula (I): wherein R 1 represents a C 3-7 alkyl group substituted by one or more fluoro or R 1 R 1 represents cyano, C 1-7 alkylsulfonyl group substituted by one or more fluoro R 3 represents cyano, or C 1 -C 6 alkyl optionally substituted by hydroxy or a group NRaRb wherein Ra and Rb independently represent H or a C 1 -C 3 alkyl group; or cyclohexyl, each of which is optionally substituted by one or more groups selected from hydroxy, fluoro or an NRc R d group wherein R c and R d independently represent a C 1 -C 3 alkyl group; and is an optional additional bond between positions 6 and 7. R 4 represents chloro, fluoro, cyano or methyl η is 1, 2 or 3 and each R 4 is independently selected when η> 1. Pharmaceutically acceptable compound and salts thereof according to claim 1, characterized in that it is represented by formula IA: wherein R1 represents a C3-7 alkyl group substituted by one or more fluoro or R1 represents a C1-7 alkylsulfonyl group substituted by one or more fluoro R2 represents cyano or a C1-C4 alkyl group optionally substituted by hydroxy or a group NRaRb wherein Ra and Rb independently represent H or a C1-C3 group R3 represents piperidin-1-yl or cyclohexyl each of which is optionally substituted by one or more selected groups of hydroxy, fluoro or an NRcRd group wherein Rc and Rd represent H or a C1 -C3 alkyl group; R4 represents chloro, fluoro, cyano or methyl; eη is 1, 2 or 3 and each R4 is independently selected when η> 1. Pharmaceutically acceptable compound and salts thereof according to claim 1, characterized in that it is represented by formula IB: wherein R1 represents a C3-C7 alkyl group substituted by one or more fluoro or R1 represents a C1-7 alkylsulfonyl group substituted by one or more fluoro R2 represents cyano or a C1-C4 alkyl group optionally substituted by hydroxy or a group NRaRb, wherein Ra and Rb independently represent H or a group C1 -C3 alkyl R3 represents piperidin-1-yl or cyclohexyl, each of which is optionally substituted by one or more groups selected from hydroxy, fluoro or an NRcRd group, wherein Rc Rd independently represents H or a C1-C3 alkyl group; R4 represents chloro, fluoro, cyano or methyl; eη is 1, 2 or 3 and each R4 is independently selected when> 1. Compound according to any one of the preceding claims, characterized in that R1 represents a C1-7 alkylsulfonyl group substituted by one or more fluoro. Compound according to any one of claims 1 to 3, characterized in that R 1 represents a C 3 -C 7 alkyl group substituted by one or more fluoro. Compound according to any one of claims 1 to 3, characterized in that R 1 represents a C 3 -C 5 alkylsulfonyl group, terminally substituted by one or more fluoro. Compound according to any one of the preceding claims, characterized in that R represents methyl or hydroxymethyl. Compound according to any one of the preceding claims, characterized in that R represents methyl. Compound according to any one of the preceding claims, characterized in that R represents piperidin-1-yl. Pharmaceutically acceptable compound and salts thereof according to any one of the preceding claims, characterized in that R4 represents 2-chloro when η is 1 or R4 represents 2,4-dichloro or 2-chloro-4-fluoro when η is 2 . 11. A compound characterized in that it is selected from one or more of the following: -4- [1- (2-chlorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5,6, -4- [1,3- (2,4-dichlorophenyl) -7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-yl] phenyl 3,3,3-trifluoropropane-1-sulfonic acid ester; 3-methyl-4-oxo-5-piperidin-1-yl-4,5,6,7-tetrahydro-1H-pinOlo [3,2-c] pyridin-2-yl] phenyl acid ester 3,3, 3-trifluoropropane-1-sulfonic; 4- [1- (2-chloro-4-fluorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5,6,7-tetrahydro 3,3,3-trifluoropropane-1-sulfonic acid -1H-pyrrolo [3,2-c] pyridin-2-yl] phenyl; -1- (2-chlorophenyl) -3-methyl-5-piperidin-2-one 1-yl-2- [4- (4,4,4-trifluorobutoxy) phenyl] -1,5,6,7-tetrahydropyrrolo [3,2-c] pyridine-4-one; -4- [1- ( 2-chlorophenyl) -5- (2-hydroxycycloexyl) -3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pinOlo [3,2-c] pyridin-2-yl] phenyl ester 3,3,3-trifluoropropane-1-sulfonic acid; -4- [1- (2,4-dichlorophenyl) -5- (2-hydroxycycloexyl) -3-methyl-4-oxo-4,5,6, 7-Tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-yl] phenyl ester of the 3,3,3-trifluoropropane-1-sulfonic acid; -4- [1- (2-chlorophenyl) -5- (3-hydroxycycloexyl) -3-methyl-4-oxo-4,5,6,7- tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-yl] phenyl 3,3,3-trifluoropropane-1-sulfonic acid ester; -4- [1- (2-chlorophenyl) -5-cyclohexyl] 3,3,3-Trifluoropropane-1-sulfonic acid 3-methyl-4-oxo-4,5,6,7-tetrahydro-β-pyrrolo [3,2-c] pyridin-2-yl] phenyl ester; -4- [1- (2,4-dichlorophenyl) -3-methyl-4-oxo-5-piperidin-1-yl-4,5-dihydro-1 H -pyrolo [3,2-c] pyridin-2-one yl] phenyl 3,3,3-trifluoropropane-1-sulfonic acid ester; -4- [1- (2,4-dichloro-phenyl) -5- (2-hydroxy-cyclohexyl) -3-methyl-4-yl 4,3,3-trifluoropropane-1-sulfonic oxo-4,5-dihydro-1H-pinOlo [3,2-c] pyridin-2-yl] -phenyl ester; chloro-phenyl) -5-cyclohexyl-3-hydroxymethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-yl] phenyl acid ester 3,3 1,3-trifluoropropane-1-sulfonic; 4- [1- (2-chlorophenyl) -5-cycloexyl-3-hydroxymethyl-4-oxo-4,5-dihydro-1H-pyrrolo [3,2-c] pyridin 3,3,3-trifluoropropane-1S-2-yl] phenyl ester -4- [1- (2-chlorophenyl) -5- (2-hydroxycycloexyl) -3-hydroxymethyl-4-oxo-4,5-dihydro-1H-pinOlo [3,2-c] pyridin-2-one 3,3,3-trifluoropropane-1-sulfonic acid phenyl] -4- (3-methyl-4-oxo-5-piperidin-1-yl-1-o-tolyl-4,5,6, 7-tetrahydro-β-pyrrolo [3,2-c] pyridin-2-yl) phenyl 3,3,3-trifluoropropane-1-sulfonic acid ester; el- (2,4-dichlorophenyl) -3-methyl-5-piperidin-1-yl-2- [4- (4,4,4-trifluoro-butoxy) phenyl] -1,5,6,7-tetrahydro -pyrrolo [3,2-c] pyridin-4-one. Compound of formula I according to any one of claims 1 to 11, characterized in that it is for use as a medicament. Pharmaceutical formulation, characterized in that it comprises a compound of formula I as defined in any one claim which is a pharmaceutically acceptable adjuvant, diluent, carrier. Use of a compound of formula I as defined in any one of claims 1 to 11, characterized in that it is in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia and bipolar disorders, anxiety, anxiety disorders, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders, epilepsy, and conditions related to neurological disorders such as dementia, neurological disorders, Parkinson's disease, Huntington's chorea, and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal and prolonged systems, indications of addiction and / or relapse. A compound according to any one of claims 1 to 11, characterized in that it is for use in the treatment of obesity. Process for the preparation of a compound of formula I according to claim 1, comprising reacting the compound of formula II wherein R, R, R and η are as previously defined in claim 1, with a compound of formula III wherein R1 is as previously defined in claim 1 and X represents a leaving group in an inert solvent, in which: presence of a base at a temperature in the range of -25 ° C to 150 ° C. Compound, characterized in that it is of formula II as defined in claim 16.